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Acute Pain and Opioids: Through the Ages
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Acute Pain and Opioids: Through the Ages
PAM MACINTYRE BMedSc, MBBS, FANZCA, MHA, FFPMANZCA
Director, Acute Pain Service, Royal Adelaide Hospital, Adelaide
Dr Macintyre is the Director of the Acute Pain Service at the Royal Adelaide Hospital, a
position she has held since establishing the service at the start of 1989. She is a
Foundation Fellow of the Faculty if Pain Medicine (FPM), a past FPM Board Member, and
a past examiner for both ANZCA and the FPM. She chaired the working party responsible
for the production of the acute pain guidelines, Acute Pain Management: Scientific
rd
Evidence, published in 2005; the 3 edition will be published in 2010. Her recent
rd
publications include the 3 edition of Acute Pain Management: a Practical Guide (with Prof
nd
Stephan Schug) in 2007 and she is currently working on the 2 edition of a coedited book,
Clinical Pain Management: Acute Pain. Her interests include acute pain management in
more complex patients (eg. opioid-tolerant patients, the elderly patient), acute non-surgical
and acute neuropathic pain, and persistent postsurgical pain.
This paper is based on a presentation given at the 2006 annual scientific meeting of the
Australian Pain Society: the theme of the meeting was ‘Pain Across the Life Span’.
Opioids have been used for the management of pain for many hundreds of years. However,
most of our understanding of the science of how these drugs work and how they are best used in
the acute pain setting is very recent.
HISTORY OF THE USE OF OPIOIDS IN PAIN MANAGEMENT
th
Up until the 19 century
Opium has been used, at least for its psychological effects, for centuries. Sumerians, who
th
lived over 5000 years ago in what is now modern day Iraq, called it the ‘joy plant’. In the 8
century BC their direct descendants, the Assyrian-Babylonians, were aware of its analgesic
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effects as well as its sedative and hypnotic properties. Hippocrates was known to have
2
prescribed the drug but it would seem that he used it mainly for ‘diseases of women’.
The earliest written reference describing the use of opium as an analgesic is thought to have
1, 2
Often called the founder of Greek
come from Theophrastus, a pupil of Plato and Aristotle.
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botany, Theophrastus wrote a large number of treatises on botany in the 3 century BC. Two of
his writings, De plantis and De causis plantarum, were translated into Latin and include a
description of the properties of opium and its medical uses, including its use as an analgesic.
Pre-modern physicians seemed to have a good idea of the effects of opium and based their
knowledge on the experiences of others. However, in the absence of evidence, did they always
use the drug appropriately? The practices of physicians around the time of Hippocrates were
3
examined by Prioreschi and colleagues in 1998. To assess the effectiveness of historical drug
administration practices they used what they called the efficacy quotient, or EQ. Their formula
was based on the number of times a drug was used ‘correctly’ – i.e. correctly in the modern
sense according to known physiological effects – and the number of times it was used incorrectly.
As examples, a physiologically appropriate use for opium would include its administration for joint
pain and headache, even though opioids may not be thought of as appropriate first-line treatment
for these in today’s clinical setting: inappropriate use of opium included it’s prescription to dry up
a runny nose.
An EQ of 1 would indicate that the drug was used as often for appropriate conditions as for
inappropriate ones. When these authors examined 150 uses of opium outlined in the Hippocratic
Corpus, they calculated an EQ of 1.08 and concluded that Hippocratic physicians used the drug
in a fairly indiscriminate way, even though they knew of its physiological effects – i.e. analgesia,
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somnolence, constipation and mood alteration.
That said, it is highly possible that they could do exactly the same calculations on the way
opioids are sometimes used today – not always in the right dose and not always for the
appropriate reasons – and they could conclude that opioids are sometimes still used in
indiscriminate ways and without evidence of benefit. For example, some patients today are
prescribed huge doses of opioid for management of their chronic noncancer pain even though
opioid use may not be appropriate and even though this practice may result in opioid-induced
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hyperalgesia.
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There were very few changes in the ways in which opium was used for pain relief over the
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next few hundred years. Up until the start of the 14 century, opioids could be prescribed by
physicians who had trained in University medical schools, surgeons (generally lay people and
considered to be of inferior status), medical practitioners (also lay people) and apothecaries; later,
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French kings restricted the prescribing of opioids – and laxatives – to physicians only.
One scholar, Roger Bacon, who lived in Paris at this time (he died in 1294), believed there
were two main problems with physicians when it came the use of opium. He said ‘(They are
ignorant) of the relation of the quantity of noxious drugs and the body, nor is the method of giving
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them known, nor what quantity for which condition or age’. He was quite correct, but these
deficiencies in knowledge would not start to be addressed until some 700 years later.
Despite opium being in common use from that time on for the treatment of pain, and for the
treatment of numerous other ailments, even basic forms of investigation into the use of this drug
th
did not start until the 17 century – the time when there were a great many advances in a number
of scientific disciplines.
Although Sir Christopher Wren is best known as an architect (for example, for St Paul’s
Cathedral and the many other buildings he designed after the Great Fire of London), he began
his career after training as a mathematician and physicist and at one stage was a professor of
6
astronomy. By the age of 17 he had invented, among other things, a pneumatic engine, a
weather clock or barometer, and a new language for the hearing impaired. In 1662, he joined
other mathematicians, scientists and scholars to form the Royal Society of London for Promoting
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Natural Knowledge, under a charter granted by Charles II.
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As outlined by Gibson, Wren, in 1656, became the first person to describe the intravenous
injection of a number of substances including wine, ale and a variety of drugs. With the help of
the famous physicist, Robert Boyle, he did this using a goose quill and pig’s bladder, and one of
the drugs he injected was opium. Details of his experiments were only published many years
later, in 1665, in the first volume of the Philosophical Transactions of the Royal Society. Included
in the notes is a description of the technique used to inject opium and crocus metallorum (an
antimony sulphate preparation used at the time as an emetic) into dogs ‘by making ligatures on
the veins and then opening them on the side towards the heart, and by putting into them slender
syringes or quills, fastened to bladders containing the matter to be injected …. whence the larger
vessels that carry the blood are most easy to be taken hold of’.
Wren also noted that the opium was ‘soon circulated into the brain, and did within a short time
stupefy but did not kill the dog’. He suggested the technique could be used for anaesthesia, but
as his study was to examine the feasibility of injecting fluids intravenously, he did not emphasise
it or pursue it. Wren also experimented with canine blood transfusions and worked with Thomas
Willis, of cerebral artery Circle of Willis fame, as well as Robert Boyle.
th
th
Towards the end of the 18 century and the first part of the 19 century, some exciting
discoveries were made in the field of pharmacology. Not least of these was the isolation of
morphine from opium by Sertürner in 1803/1804. He coined the name morphium (later changed
to morphine), after Morpheus, the Greek God of dreams. Another 50 years on, the administration
and efficacy of morphine was greatly improved by the introduction of the hypodermic needle and
syringe. These were developed by Wood based on a design already manufactured by a Mr
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Ferguson – a local London chemist.
The history of the parenteral administration of morphine has been summarised by Hamilton
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and Baskett. Wood was the first to inject morphine subcutaneously (SC), intending to produce a
local analgesic effect in a painful area. Apparently he was somewhat annoyed, when he checked
the next morning, to find the patient was unconscious. He had noticed the systemic effects but
still believed that pain relief resulted from morphine’s local effects. It took a London surgeon,
Charles Hunter, to realise that it did not matter where the SC morphine was injected, the result
was pain relief. Following the ensuing prolonged and often acrimonious discussion between the
two in letters to the Lancet and the British Medical Journal, a committee of the local Medical and
Surgical Society (now the Royal Society of Medicine) was formed to settle the argument; it
concluded that the systemic effects of an injection of morphine were of most importance.
Oral opium was first used for postoperative pain relief by London surgeon James Moore in
1784; the first report of SC morphine injections (using a syringe) for postoperative analgesia was
by James Paget in 1863 – he suggested 15-30 mg doses, huge in comparison to doses used
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1, 8
today. There were also case reports of the use of intrathecal morphine as early as 1901.
Records showing other early use come from the Dundee Royal Infirmary in the UK: in the period
1909-1910, apparently 35 spinal anaesthetics were given in one year: 9 contained morphine,
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Acute Pain and Opioids: Through the Ages
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presumably given for postoperative pain relief. This technique seemed to fall out of favour
relatively quickly. It might have had something to do with the very large doses (e.g. 10 mg) used
then compared with the doses used today.
The 1930s to 1950s
Up until this time the use of morphine for pain relief was widespread, but there was still no
good evidence about the optimal dose, how best it might be given, how effective it might be in
different circumstances or how they worked. That is, the concerns that Roger Bacon had
th
expressed in the 13 century, had not yet been addressed.
In the early 1930s, there was increasing interest in basic research relating to pain relief. For
example, an analgesia program was established at the National Academy of Sciences in the US
(the precursor of the NIH), for the purpose of investigating the chemistry and pharmacology of
analgesics and then testing them in laboratory animals followed by tests on humans in the clinical
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setting. They decided to start their program by looking at the alkaloids of opium. By the end of
the first 10 years of the program they could relate the molecular structure of opioids to
pharmacological activity – both of the standard drugs, morphine and codeine, as well as novel
opioid compounds. They recognised that alterations in chemical structure could often result in
predictable changes in pharmacological effect and had also synthesised new opioids such as
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oxycodone, methadone and pentazocine.
The 1950s
The 1950s were also marked by significant innovations – this time in research methodology –
innovations that would help significantly in the understanding of opioids. These included the
mouse hot-plate method that would complement the tail-flick procedure developed in 1942, two
procedures that have become standard tools for assessment of the antinociceptive effects of
1
opioids in rodents. The coaxial stimulated guinea pig ileum preparation was also developed in
1955 – a preparation later used in the discovery of the presence of enkephalins in animal
1
tissues in 1974. The 1950s also saw the introduction of the double-blind study, which greatly
contributed to the reduction of experimenter and patient bias, especially in drug evaluation
1
trials.
From the advances that were made in stereochemisty and knowledge about drug molecules
and composition during this time, it was also becoming apparent that some drugs, like opioids,
probably worked by interacting with receptors.
But 100 years after morphine was first given by SC injection, and many thousands of years
after it was first used for pain relief, albeit as a component of opium, no one had tried to establish
the best dose to give.
10
In 1954, one such study was performed by Lasagna and Beecher. They compared doses of
10 mg and 15 mg of morphine per 70 kg body weight, injected subcutaneously. As the larger
dose had the higher incidence of side effects they declared that 10 mg was the optimal dose. The
idea of the study was good – the conclusion not so. This idea of fixed doses or fixed doses per
kilogram body weight unfortunately persisted for years. Also, unfortunately, these authors
cautioned against flexibility in dosing because of the possibility of dangerous side effects, and
warned against higher doses because of the risks of dependence.
The 1960s
Basic research into opioids advanced very rapidly at this time. Large scales studies on the
mechanisms of dependence were made possible by the development of animal models of opioid
1
dependence. The opioid antagonist naloxone was also synthesised – a drug that would prove
not only to be invaluable in the clinical setting, but would later be used by Snyder and Pert to
11
identify opioid receptors in the brain.
In addition, very basic forms of patient-controlled analgesia (PCA) had been introduced for the
12
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relief of postoperative and labour pain.
The 1970s
The very big advances in the knowledge of how opioids worked came in the 1970s. Firstly in
1973, was the demonstration by Snyder and Pert, using tritium labelled naloxone, of opioid
11
14
receptors in the brain. This was followed by the identification of endogenous opioids in 1975.
In the same year Laurie Mather’s group published the first of a series of papers on the
15, 16
It was
pharmacokinetics and pharmacodynamics of opioids administer by different routes.
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somewhat amazing, that up until this time, there was not a proper scientific basis for these
common clinical methods of opioid administration.
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In 1976, Yaksh and Rudy showed that morphine injected into the subarachnoid space in a
variety of animals resulted in pain relief that was dose-dependent and reversible with naloxone.
18, 19
and others were able to show that opioids exerted their action
Just a year after this, Snyder
through selective opioid receptors located in both the brain (especially in the limbic system and
periaqueductal gray area of the brainstem) and the spinal cord (particularly in the substantia
gelatinosa) – that is, that pain relief from opioids could be mediated at both sites.
The demonstration of opioid receptors in the spinal cord was followed within a very short time by
20
21
reports on the clinical use of spinal and epidural opioids.
OPIOIDS AND ACUTE PAIN MANAGEMENT - THE 1980’S ONWARDS
Newer acute pain management techniques and Acute Pain Services
In the 1980s the use of epidural morphine for postoperative analgesia became commonplace.
22
At this time, PCA, first developed by Sechzer in the early 1970s, also started to become part of
routine (usually postoperative) pain management rather than primarily confined to experimental
23
settings. In large part, the introduction of Acute Pain Services (APSs) in the late 1980s helped
the use of newer techniques such as these to become widespread.
By the 1990s, opioids had been given by virtually every route imaginable in attempts to treat
acute pain. Not just intravenously and spinally, but intranasally, transmucosally, by intra-articular
injection and inhaled.
Has the patient benefited?
Have these recent advances helped patients to become more comfortable?
Recent meta-analyses have shown the PCA results in better analgesia than opioids given by
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intramuscular (IM) injection – but only slightly. The results of these meta-analyses were a little
unexpected but could reflect two things. Firstly, in an experimental setting, it may be that the IM
opioids were given truly on demand and therefore would be expected to be relatively effective.
The other reason could be that in most studies, the size of the bolus dose of morphine delivered
by the PCA machine is limited, often to just 1 mg. By limiting the inherent flexibility of the
technique and giving all patients access only to a fixed bolus dose, he potential effectiveness of
the technique is also restricted. PCA should not be used as a ‘one size fits all’ method of pain
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relief.
Epidural analgesia, on the other hand, consistently results in significantly better pain relief
compared with IM opioid analgesia – whether opioids and local anaesthetics are used alone or in
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combination. It has been difficult to show better patient outcomes following the use of epidural
analgesia for acute pain. However, such evidence as does exist points to the need to include
local anaesthetics in the solution used if better outcomes are to be achieved. With this
combination, improvements in postoperative respiratory, cardiac and bowel function have been
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reported.
Another look at opioid doses
Suggestions for the optimal dose of an opioid had changed little from the days of Lasagna and
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Beecher. However, results of early APS audits suggested that the doses of both epidural and
27
parenteral opioids were better based on the age of the patient than their weight. Audit results of
PCA use also showed that there was a huge interpatient variation in the dose of opioid required
27
to achieve analgesia and that rather than cautioning against flexibility is dosing because of the
possibility of dangerous side effects, and warning against higher doses because of the risks of
27
dependence, as was suggested by Lasagne and Beecher, better pain relief would not be
obtained unless a wide variation in doses was tolerated and pain relief titrated to the individual
patient.
The magnitude of this variation in opioid dose as patient age increases is much greater than
can be accounted for by the age-related changes in physiology that are seen in older patients.
While there are alterations in renal and hepatic function and cardiac output, which will in turn alter
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drug pharmacokinetics, it appears to be a primarily pharmacodynamic phenomenon.
29
This had been demonstrated in a study by Scott and Stanski. They looked at both the
pharmacokinetic and pharmacodynamic components of (anaesthetised) patient responses to
alfentanil and fentanyl infusions. The doses given were those required to produce the same EEG
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Acute Pain and Opioids: Through the Ages
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stage. They found that there were no age-related changes in pharmacokinetics but that the
amount of opioid to produce this EEG effect decreased as patient age increased. In fact, there
was a 50% decrease in dose required, or a 50% increase in brain sensitivity to opioids, from age
20 to 89.
The reasons behind these changes are not yet clear. However, it is known that in rats, ageing
is associated with reductions in opioid receptor density and increases in opioid receptor affinity.
In general, there are also age-related changes in synthesis, axonal transport, uptake and
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receptor binding of many neurotransmitter systems.
At the other end of the lifespan, age also appears to be the most important factor determining
opioid requirements. Marked changes are seen in the dose requirements and responses to
opioids in premature and term neonates and infants. In the laboratory, rat pups are much more
sensitive to the effects of morphine than older rats. This probably results from a number of
factors, including developmental changes in the opioid receptor (including expression, distribution
30
and function) and changes in the way the developing nervous system processes pain. Pain
processing in the immature peripheral and CNS is very different from the mature one.
In the clinical setting, neonates and infants also seem to be more sensitive to morphine given
30
for postoperative pain . In older children, average PCA morphine requirements also change with
31
age.
RECENT ADVANCES
New ways to administer opioids continue to emerge. One of the more recent is the
development of an extended-release epidural morphine preparation that, once injected, can
32
33, 34
This
provide pain relief for up to 48hr. Another new technique is iontophoretic fentanyl PCA.
system uses a small electric current to speed transfer of drug across the skin. In the case of
fentanyl, it means that peak blood concentrations may be seen within minutes or so, compared
with many hours when traditional trandermal fentanyl delivery systems are used.
Extended-release epidural morphine
An advantage of the extended-release epidural morphine preparation is that only a single
dose is needed, which means that epidural catheters are not - possibly of benefit in patients
prescribed thromboprophylatic heparin in the postoperative period. However, administration of a
single dose also means that there is no opportunity for individual patient titration. There also
appears to be a high reported incidence of respiratory depression, but this may be an inaccurate
estimate as it would seem that many investigators still define respiratory depression as a
decrease in respiratory rate, when this is known to a less reliable indicator than increasing
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sedation. The preparation it is intended for lumbar administration only and combination with
local anaesthetics is not advised. As noted above, where there is evidence of better patient
outcome after epidural analgesia, local anaesthetics seem to be an important component of the
solution used.
Iontophoretic fentanyl PCA
This system delivers a preprogrammed bolus dose when activated – as does the commonly
used IV PCA system, but no IV lines are required. However, the size of the bolus dose is fixed
and therefore it may not provide the flexibility of dosing that is needed in the acute pain setting.
With IV PCA bolus doses, the size of the bolus dose can be readily altered – with this new system
it can not.
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It has been shown to be as effective as ‘standard’ IV PCA morphine. This means that the
comparative studies limited the size of the IV PCA morphine bolus dose to 1 mg. It is known that
for PCA to be more effective, the bolus dose often needs to be greater than this – and also
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sometimes smaller. IV PCA is not a one size fits all technique.
WHERE TO NOW?
Although opioids have been used to treat pain for thousands of years, problems with their use
remain. Because of the enormous interpatient variation in dose requirements, effective pain relief
will still require titration of opioid dose, regardless of route, for each patient. There will still be
issues relating to the side effects that can result from opioid administration as well as problems
related to the development of tolerance and opioid-induced hyperalgesia.
Will there be better opioids – maybe opioid agonists with high selectivity for different receptor
types? Will there be better ways to treat side effects? Or will improved analgesia with opioids
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result from combination with other drugs that can modulate opioid receptor mediated effects such
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as ketamine, naloxone, CCK antagonist or maybe a newer drug such as F13640, a 5HT-1A
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receptor agonist?
Only time will tell whether any of these advances will be as clinically significant as those made
over the previous 3-4 decades.
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